Hypoxia increases leptin expression in human PAZ6 adipose cells

AIMS/HYPOTHESIS: Leptin, an adipose tissue-derived cytokine involved in the control of body weight, also participates in a variety of biological functions, including angiogenesis. Because reduced oxygen availability is a major inducer of angiogenesis, we hypothesized that low cellular oxygen tension could regulate leptin expression in adipose cells. METHODS: Differentiated PAZ6 adipocytes were cultured for 48 h in the presence of chemical inducers of cellular hypoxia (cobalt chloride or desferrioxamine) or in an atmosphere containing only 6% oxygen. The effect of hypoxia on the expression of leptin and several adipose genes was assessed by semi-quantitative RT-PCR. The effect of hypoxia on leptin promoter activity was tested in PAZ6 cells transiently transfected with a luciferase reporter construct, containing 1.87 kb of the human leptin promoter. Leptin secretion in the culture medium was determined by radioimmunoassay. RESULTS: Hypoxia increased leptin mRNA expression, leptin promoter activity and leptin secretion in the culture medium by two- to threefold ( p<0.05). The expression of the glucose transporter isoform 1 (GLUT-1) mRNA, a well known hypoxia inducible gene, was also increased. In contrast, glucose transporter isoform 4 (GLUT-4), hormone sensitive lipase (HSL), fatty acid binding protein (aP2) and uncoupling protein 2 (UCP2) mRNAs were markedly reduced by hypoxia. In addition, a similar hypoxia-induced increase in leptin mRNA and secretion was observed in primary rat adipose cells. CONCLUSION/INTERPRETATION: Hypoxia markedly and specifically increased leptin gene expression through activation of the leptin gene promoter, and this resulted in an increased leptin production by human PAZ6 adipocytes.